Wednesday, June 29, 2011

"Scathing" was the way that Kerry Sheridan of AFP:http://news.yahoo.com/us-bone-growth-studies-under-fire-alleged-bias-222210731.html--described the editorial that's just now appearing in The Spine Journal, authored by a number orthopedists plus Dr. David J. Rothman of Columbia. (Note: The article is apparently to appear in the June issue of the journal which seems not yet to be up on the journal's website. One needs a subscription to access the site.)

Necessary background--this brings us back to our old friends the device company Medtronic (see most recently http://brodyhooked.blogspot.com/2010/12/in-defense-of-paranoia-suspecting.html). In previous posts I discussed in very general terms the fact that this firm sells "hardware" for spinal fusion surgery and has been implicated in a number of shady practices that have been exposed by John Fauber at the Milwaukee Journal-Sentinel, among others, and also earned them the close interest of Sen. Charles Grassley's subcommittee. I have not as yet focused on a specific product called Infuse (or generically, rhBMP-2). This chemical is a bone growth factor that is applied to bone to make new bone grow. It is supposed to be enclosed in a little cage so that it causes the bone to grow only where the surgeon wants it to. The big advantage is to cause new bone to grow, for example to fuse two vertebrae togerther, instead of having to make a separate incision and take a bone graft from another site (like the hip) for the same purpose.

The authors of this editorial begin by noting a series of 7 published reports (one of which was published in their own journal) about Infuse, all by authors with significant financial ties to the manufacturer--they state that one trial in particular apparently paid its investigators a cool $26M. These reports are quite remarkable in one way--not a single adverse reaction is attributed to the product. Think of that. Ever heard of anything in medicine that never, ever, produces even one adverse reaction?

Not surprisingly, as soon as articles began to be published by those not in the pay of Medtronic, toxic effects began to be reported--the short list includes inflammatory reactions, persistent pain, inability to urinate, inappropriate abnormal bone growth, and displacement of the implanted apparatus. The major systematic review published in the same issue of the journal estimated that actual complications and adverse events "are perhaps 10 to 50 times the original estimates calculated from industry-sponsored studies" by the FDA.

The editors now face squarely the implications for their own practices. They allude to what they call the "choirboy defense" that all physicians are of stellar integrity, potential conflicts of interest are only potential, etc. This defense, they conclude, won't pass muster, either inside or outside of medicine. Add to this is the problem that "disclosures in our journals are more often than not self-contradictory blurbs of improbable nonsequiturs bracketed by misdirection." They use as an example a published disclosure statement which is actually a denial rather than a disclosure, stating both that the manuscript is not about medical devices or drugs, and that "no benefits in any form have been or will be received from a commercial party." The editors then state, "Even a most cursory review shows that this was all about devices and drugs used in an off-label manner and reported by authors who, by conservative estimates, have tens of millions of dollars of financial association with the sponsor."

The editors conclude, "The core of our professional faith...is to first do not harm. It harms patients to have biased and corrupted research published." Saying "We all must do a better job going forward," they promise a series of later changes to be announced to improve their editorial policies.

Comment: First, kudos to the editors of The Spine Journal for so frankly throwing down the gauntlet for themselves. Second, I am not a business ethicist, but I have to borrow a note from my old friend Leonard Weber in his nice book about the pharmaceutical industry, Profits Before People? I believe that Professor Weber would ask--how can it possibly benefit Medtronic to run its business in this fashion? How could any business plan, other than the most cynical short-term stockholder gain (maybe with the CEO exiting via the famous golden parachute), include exposing one's firm to this barrage of apparently-fully-justified criticism and condemnation? Or has the idea of "in the long run" so totally ceased to function in American culture?

For a number of years the Council on Ethical and Judicial Affairs (CEJA) at the AMA has been proposing new opinions on the ethics of the relationship between physicians and the drug industry, along the lines of the reforms advocated in this blog. The existing AMA opinion on the topic is, in my own view, quite wimpy and offers all sorts of loopholes to excuse docs taking bennies from the drug industry. You can read it here:http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion8061.page?That opinion dates from 1992. Several times in recent years, CEJA has offered revised and updated opinions that come down more strictly on policing the conflict of interest inherent in docs accepting gifts/bribes from Pharma. Each time the report was sent to the House of Delegates, and each time the HOD slapped it down and sent it back to CEJA for rewriting. This is a perennial problem in the AMA--in this sense the HOD is too democratic. It seems that if CEJA tries to say something is ethically improper, and if any significant number of Delegates currently do it, the question shifts from the reasonableness of the ethical principle to "how dare my AMA tell me that I'm unethical!" So it can become an ethical race to the bottom instead of aspiring to higher levels of professionalism. (PS: Since the AMA seems to employ a webcrawler to alert them to any mention of their organization on the Internet, you can expect a comment to appear below from the AMA president, in about 3.6 seconds, informing us that what I just said is unfair and not representative of the AMA's good works. For previous comment like that see:http://brodyhooked.blogspot.com/2011/04/supremes-to-hear-challenge-to-vermont.html)

In a similar vein, CEJA proposed back in 2009 a report specifically on commercial sponsorship of continuing medical education programs:http://brodyhooked.blogspot.com/2009/06/ama-council-cuts-cme-baby-in-half.html--which the HOD rejected, presumably on a matter of technical language. But some inferred from the HOD action that really, the organization was not all that interested in ending the commercial sponsorship gravy train, that currently keeps many state medical society meetings (for example) afloat financially.

So when CEJA came back with a revised CME report, this time really strict on cutting the financial ties with industry, I would have guessed it would get the same frosty reception from tghe HOD. To my surprise Dr. Carlat tells us that the new report actually passed and has become official AMA policy. Not only that, but because of the relationship betweeen the AMA and the Accredition Council for Continuing Medical Education, the national group that certifies CME programs for official credit-granting status, this change immediately impacts ACCME policy as well. The CEJA opinion (see link on Dr. Carlat's blog) cites particularly the recent Institute of Medicine report on conflicts of interest that similarly proposed elimination of commercial funding for CME, as we reviewed:http://brodyhooked.blogspot.com/2009/05/iom-report-on-coi-yes-we-really-mean-it.html

Dr. Carlat adds some notes of caution, in that the report does allow for some commercial sponsorship to continue. The exceptional case they seem to contemplate is when a new medical device is introduced, which is very expensive, and the only people who really know how to train docs in its use are the employees and consultants of the company that manufactured it. They give a number of reasonable precautions to keep commercial sponsorship limited to these unusual types of situations, and also to further mitigate the biasing effects of that sponsorship even when it is allowed. In short, I think Danny Carlat is right to call this a very significant breakthrough from an unexpected quarter.

As a nonlawyer reading the Supreme Court opinion, I was struck by the very different logics applied by the majority and the dissenters. (By the way, in my prediction, I foresaw a 5-4 vote, but the actual vote was 6-3, with Justice Sotomayor going over to the conservative side--so much for "liberal" justices.)

The majority opinion, written by Justice Kennedy, starts with the now-widely argued position that "commercial speech" is nearly as well respected as a First Amendment right as is any other form of speech. The question then is whether the Vermont law is written narrowly enough, and cites a sufficiently compelling state interest, to justify its interferences with commercial speech. (Which in the old days we used to call "advertising.")

Based on the fact that pharmaceutical marketers find the prescriber data sold by the respondent, IMS Health, to be sufficiently worthwhile to pay big bucks for, the majority hold that drug detailing is commercial speech, and that the Vermont statute burdens this commercial speech (by interfering with the data mining that makes the speech more effective). It is at this point that the majority get their knickers in a knot, because the Vermont law would allow the selling of prescriber-identifying data for other purposes, such as public health monitoring or research. The offense here, in the view of the court majority, is that Vermont will allow speech when it likes the message, and disallow speech when it does not like the message (that is, when the speech favors prescribing high-price drugs). This seems too much like censorship and raises all the First-Amendment hackles of the justices.

An example Justice Kennedy offers seems to hint at what most offended the majority. They note that in Pennsylvania, this same sort of prescriber information was used by a state agency engaged in counter-detailing--that is, going to doctors with a message about prescribing cheaper generic drugs. This usage of the data would also be allowed by the Vermont law (though as Justice Breyer wrote in his dissent, there's no evidence that any such counter-detailing is actually going on in Vermont). So we have a situation where the use of a type of information is prohibited by law when the drug companies wish to sell their products, and is allowed by law when somebody wants to come to docs with a message not to prescribe the drug company's products. This seems to the majority to be so unfair on its face that the law is proclaimed to be unconstitutional. As typically occurs in legal decisions that by the merest chance end up serving the interests of powerful corporations, the relative power and economic muscle of the two parties being discussed here does not enter into the equation at all.

Speaking for the three dissenting justices, Justice Breyer offers a contrary view which seems to have the virtue of logic and good sense on its side--but that's probably just me. Breyer asks: exactly what is it about the Vermont law that interferes with drug companies getting their marketing message out? They can print ads, advertise on TV, hold dinners to push their drugs, and send as many detailers to docs' offices as often as they wish. All the law says is that companies cannot sell a type of data that makes these marketing efforts especially effective. Basically Breyer is saying that the whole framing of the issue by the majority, as interference with speech (commercial or otherwise) is bogus. He goes on to say that the stated goals of the law--improving public health, reducing health costs, and protecting doctor privacy--are fully sufficient to justify the law, and that there is no narrower way to write the law that would properly protect these legitimate state interests.

The majority objected to the Vermont law because its restrictions were "content-based" and "speaker-based." That is, the law censors speech based on who says it and on what it says, which violates First Amendment protections. But Justice Breyer replies that what we have here is commercial activity, and the right of the state to regulate commercial activity, which no one (openly) disputes. And any regulation of commercial activity must by its very nature be content- and speaker-based. For example, the FDA is allowed by law only to regulate drug companies and similar firms, and only to regulate marketing about drugs. Well, duh.

So in my biased view, the logic is all on the side of the dissent and not the majority. But I would lose an opportunity to repeat the basic message that runs throughout this blog if I did not fully agree with one argument made by Justice Kennedy: "Physicians can, and often do, simply decline to meet with detailers... Doctors who wish to forgo detailing altogether are free to give 'No Solicitation' or 'No Detailing' instructions to their office managers or to receptionists....If pharmaceutical marketing affects treatment decisions, it does so because doctors find it persuasive."

In other words, if physicians behaved like professionals instead of industry patsies, then Vermont would not need any such law. If physicians tomorrow refused to see detailers, then IMS Health would go out of business, at least so far as its business involved data-mining.

A brief digression--a fight is brewing in Washington that in many ways is all about the future of health care cost containment in the US, whether or not "Obamacare" goes forward or is shot down in flames. The fight, which is getting much less media attention than it deserves (except for demogoguery about "death panels"), addresses Medicare's proposed Independent Payment Advisory Board (IPAB). The health reform law calls for a 15-member appointed board, made up of medical experts, to recommend to Congress how Medicare can cut costs. The goal was to re-0create for health care the Pentagon's base-closure commission, that managed to create a rational system to replace the old district-by-district Congressional bickering.

When Obama was challenged with the Ryan Plan from the House GOP, claiming to do a better job of Medicare cost-cutting (a claim later shown to be mostly smoke and mirrors), he responded with his own proposal to strengthen the role of IPAB.

Time out for a health policy announcement. If you are like any of my health-policy-wonk friends, you realize that there are basically two ways to trim Medicare costs. One is the IPAB way--try to decide on a scientific basis what works and what does not, and selectively eliminate payments for what doesn't work. Best estimate today is that if we fully implemented such a scheme we could save 20-30% of Medicare costs. The other way is the usual Congressional way--wait till a last-minute crisis, then impose an emergency across-the-board cut of so many percentage points, and don't worry if useful care gets eliminated alongside useless "care."

The predictable response of the GOP has been to denounce the IPAB as unelected bureaucrats who want to kill Grandma. But what has thrown the media for a loop (when they pay attention at all) is the group of Democratic congresspeople who have joined in GOP calls to repeal IPAB.

Jones tells us just who these "New Democrats" are--they basically have sold themselves to two major interest groups, the financial services and the health care lobbies. Their buzzword is "innovation," and they oppose meassures that are said to stifle innovation--but by the merest coincidence, what they oppose is regulations that would cut into the profits of their corporate handlers. And according to Jones, guess who's heavily investing in these House members from the industry side--Big Pharma leading the pack. Every deep-pockets interest group that now sells a lot of stuff which would not stand muster if Medicare monies were spent in accord with the best scientific evidence are lining up to try to kill IPAB, and the New Democrats are scarfing up the campaign cash.

Jones goes on to tell us how the media get suckered by people like the New Democrats because they've drunk the same Kool-Aid that Obama has, and go into raptures over anything that even vaguely looks bipartisan. But what is really bipartisan over the fact that special interest groups have bought a small bunch of Democrats retail, in the same fashion that they've bought the Republicans wholesale?

Finally, Jones reviews several political scenarios for future votes on IPAB and issues this dire prediction: "It’s hard to imagine, then, that the New Democrats will be able to repeal IPAB before the 2012 election. But, by joining with Republicans in the attempt, they may well succeed in turning Medicare from a winning issue for Democrats into a losing one." And, if that happens, look for boom times for Pharma, device companies, hospitals, and procedural subspecialists, while Medicare costs continue to bankrupt the nation (http://brodyhooked.blogspot.com/2011/06/cut-health-costs-not-in-us-of-thank-you.html).

Heidi Ledford in Nature--http://www.nature.com/news/2011/110622/full/474433a.html--describes Pfizer's June 8 announcement that it was spending $100M on a research partnership with eight Boston area academic institutions, and adds that this is only one of a number of recently announced partnerships between drug firms and academic labs. (Yours truly is quoted briefly toward the end of the article.)

The article notes a number of important issues. In recent years, as described in HOOKED, the drug industry has been pulling research support out of the academic medical centers that used to do the lion's share of the late-stage clinical trials of new drugs, electing instead to go with commercial contract research oprganizations (CROs) that can do the job quicker and without academic-administrative red tape, especially if they can outsource the trial to less-developed nations where ethical oversight may be much looser. This more recent trend, however, is to link up even more tightly with academic centers for the earlier, molecule-discovery stages of drug development: "[T]hese relationships are becoming more important as the industry closes its research labs in response to falling profits." The loss of revenue due to the drying-out new drug pipeline (see for instance http://brodyhooked.blogspot.com/2011/04/why-pharmas-new-drug-pipeline-is-dry.html) has crimped the big firms' research budgets, it seems, and sent them looking for more partners in academe.

Now, as I made clear also in HOOKED, it is nothing new for academic labs to discover promising new molecules and drug mechanisms, then to have industry swoop down later and scoop up the findings for commercial development. So why does Pfizer want to put $100M up front instead of just sitting back and letting the scientists in Boston chug along as they always have? Both sides, it seems, have realized that the old system was suboptimal. Ledford quotes Mark Pepys, an investigator in London:

"Yet industry's need for secrecy, and its tendency to change its research focus abruptly, can conflict with the more open and stable academic environment. Pepys experienced this first-hand in the 1990s when the Swiss drug-maker Roche abruptly terminated its collaboration with his team. He faced a long and costly battle to retrieve the intellectual-property rights to a compound developed during the project. A little later, Roche agreed to work on the compound with him again, only to prematurely end the collaboration a second time. Once more, Pepys had to fight to continue his work. 'It was a very expensive and tedious process that has delayed the drug by about ten years,' he says. 'And the clock on the patent is ticking.'

"Nevertheless, Pepys notes that without Roche's help, he would not have been able to develop a compound that, he hopes, will soon be ready for clinical tests in people with Alzheimer's disease. 'Nobody except big pharma can make a medicine effectively,' he says."

From their side, industry has been frustrated with previous, hands-off deals with academe:"Shiv Krishnan, a senior director at French drug-maker Sanofi's branch in Bridgewater, New Jersey, notes that Hoechst, a German life-sciences company that Sanofi acquired, paid $70 million in the 1980s to fund research at Massachusetts General Hospital. In the end, however, the firm had little to show for it, Krishnan says. 'And why?' he asks. 'Because it wasn't collaborative. It was: I'll send you the cheque and you let me know when you have something.'"

So how do the drug companies propose to fix all this? "Pfizer says it will set up a lab in Boston that will house about 50 researchers — half of them Pfizer employees, the rest Pfizer-funded postdocs from participating academic labs. The team will work on projects selected by an oversight board comprised of academics and Pfizer executives. ... The various deals also aim to smooth over tensions between industry and academia. Duncan Holmes, who heads GSK's Discovery Partnerships with Academia initiative, says that the company will give research partners a year's notice if it chooses to end a collaboration and that, if it that happens, academics would be free to continue with the project. To ease worries about publication restrictions, many agreements stipulate the terms for publication ahead of time."

As we have described at length in previous posts, research funding, per se, seems less corrupting than arrangements that put money directly into the pockets of investigators, like consulting and speakers' fees. Moreover, as Kenneth Kaitlin of the Tufts Center for the Study of Drug Development (heavily funded by industry) adds, the universities now have a stronger bargaining position due Pharma's financial stresses: "Earnings at these companies are falling through the floor and investors are losing confidence."

While I applaud the increased attention to issues that have led to loss of trust in the past, I still agree with Harvard sociologist Eric Campbell: "You should not in any way accept the notion that these giant institutional agreements are without tremendous danger." In general Ledford's piece describes most of the dangers accurately, but one could have used greater emphasis. If university labs start acting more like the drug companies' in-house research labs, we can be pretty sure what will happen to the scientist who's on the verge of discovering a new drug to treat malaria or African sleeping sickness. She'll be told to drop that project and work instead on something that grows hair on bald men, or eliminates wrinkles.

Anyway, the short version. In 1995, Johnson & Johnson funded a project led by three prominent academic psychiatrists to write Schizophrenia Practice Guidelines. Things being pretty loosey goosey back then regarding conflicts of interest, no one really made any bones about these guidelines being a tool to market the drug Risperdal (risperidone). The academics freely consulted the J&J staff and shared drafts with them. J&J for this privilege paid a total of $515K to the three medical schools where these psychiatrists were based.

Now, how to get folks to read and follow these wonderful new guidelines? The three docs then proceeded to establish a firm called Expert Knowledge Systems. EKS was set up to take drug company money, use it to publicize and advocate for the new guuidelines, and incidentally to pay some cash to the three docs, now that they had their own organization and were no longer getting the grants through their medical schools. EKS ended up taking in more than $900K from J&J.

Still back around 1996-7, EKS launched an effort with the Texas Medication Algorithm Project to help them design a drug protocol to assist state Medicaid mental health programs in designing (presumably) cost-effective ways to treat their patients with drugs. Not surprisingly, the TMAP protocol, which was then heavily peddled to other states, ended up recommending Risperdal a good percentage of the time, over cheaper generic alternatives that have since been shown to be just as effective and perhaps safer.

As I discussed in HOOKED, in 2004, a former Pennsylvania state investigator (who was fired when he started raising inconvenient questions) blew the whistle on how TMAP was really a drug-selling scam. In 2006 the Texas attorney general joined this suit, which is scheduled finally to come to trial in November.

So why all the fuss here and now? Some of the documents related to this whole debacle are only now coming to light--what I said above comes from a report from David Rothman at Columbia prepared last October (see link in Pharmalot post), though the bulk of the relevant documents in this case remain sealed. One regularly encounters objections from Pharma when we accuse them of sleazy practices--this is all old news; this stuff happened in the 1990s for heaven's sake, of course we gave up doing those things years ago. And indeed that may be true. But here we come to my old refrain--just how would we know? When only now in 2011 are we starting to find out about stuff that happened back in 1996, on the basis of what sort of faith are we to accept the assertions that nothing like this happens today? Ed Silverman points out that if J&J settles the case pretrial, one result could be that the other documents will remain out of the public eye. And Kate Petersen focuses her analysis on whether today's more stringent conflict-of-interest rules would have prevented all this from happening, and concludes that it's iffy.

Finally, a footnote. One of the three academic psychiatrists who started that ball rolling in 1996 was Dr. Allen Frances, chair of psychiatry at Duke. We have encountered Dr. Frances in these pages before: http://brodyhooked.blogspot.com/2009/06/will-psychiatrys-dsm-v-be-huge-growth.html. In that post, about psychiatry's DSM-V controversy, Dr. Frances was on the side of the angels as I depicted him, criticizing the aspects of the new DSM-V from the vantage point of his own role as a chief architect of DSM-IV, and accusing DSM-V of being way too ready to add new, dubious psychiatric diagnoses which are almost sure to increase drug prescribing across the board. For his pains, Dr. Frances was immediately condemned by his peers at the American Psychiatric Association, and accused of being motivated by conflict of interest because he had authored a book that was based on DSM-IV. Back then I trusted the statements of people like Dr. Danny Carlat that Frances was the good guy in this dispute. Had I known about this older history, I would at least have seen the logic of suspecting that Dr. Frances might have been motivated by money in the stand that he took. Whether Dr. Frances is a reformed former offender who has now seen the light, and has come over to the right side, I will leave to my psychiatry colleagues to determine.

One of the problems of being a so-called "ethicist" is that occasionally you stake out a position based on what you think are valid principles; and then somebody you agree with and whose work you admire turns out to have crossed the line you've drawn. Ethics, of course, requires that you show them no favoritism and condemn their behavior equally with those lower down your likeable list. But it can still be painful.

I have for many years been drawn to the arguments that the prescription use of opiate drugs for chronic, non-cancer pain needs to be liberalized. That is a hard case to make in our society for several reasons. One is that we live in a society that has so demonized addiction that anything about using opiates draws immediate resistance and condemnation. Another is that there is a lack of solid data, in large part because "pain" is not a disease. Most diseases have a National Institute of Health devoted to their study, but pain does not. For a long time it has been extremely hard to get research funds to really study how well opiates work for this sort of pain. We do know, however, that an incredible number of Americans say they have longstanding pain that is not being adequately treated--up to 75 million according to one survey cited by the AMA.

In HOOKED I commented on journalist Barry Meier's book, Pain Killer, about the epidemic of OxyContin abuse. Meier did a reasonable job of giving a balanced presentation of the legitimate medical uses vs. the abuses of opiates. But he came down appropriately hard on Purdue Pharma, OxyContin's manufacturer. More to my chagrin, as I admitted in HOOKED, he listed a number of national pain-management authorities whose work I had long admired, as having gotten substantial research funding from Purdue Pharma and other firms. One could make the excuse that if you wanted to do any sort of research on opiates, that might have been the only game in town, with Federal grants so hard to get. Still there was no question but that this financial tie cast a shadow on those who advocate more liberal use of opiates.

Now the other shoe has dropped. John Fauber, author of an important series of investigative pieces in the Milwaukee Journal-Sentinel, that we have previously cited several times, more recently targeted the University of Wisconsin Pain and Policy Studies Group, in an article from April that was just alluded to by Kate Petersen at PostScript:http://www.jsonline.com/watchdog/watchdogreports/119130114.html

The Wisconsin group have been national leaders in the struggle to get physicians to prescribe opiates more freely for chronic pain, and to alter government policies to reassure physicians they will not face licensing or criminal actions for responsibly prescribing opiates for legitimate pain patients. Fauber targets two leaders of the UW group, Aaron Gilson and David Joranson. He documents that both have received finding from Purdue Pharma and other drug firms that goes beyond research support and even general program support, working as paid consultants and speakers. Documents that they contributed to on pain policies often did not acknowledge that financial tie. In short, the same old incestuous relationship we've seen with so many other academics in this blog.

Fauber tries to put all this in perspective by painting a picture of a society that is now suffering huge burdens from the abuse and diversion of prescription opiates, due to the misguided prescribing practices of doctors who use OxyContin and its cousins for headaches and back pain, when the medical literature provides no sound basis for such use--an epidemic of drug problems aided and abetted by the reports and articles published by the Wisconsin pain center. Now this is partly true--there is indeed a serious increase in the abuse of prescription opiates, and in to some degree thay have become more popular among some user populations than older drugs of abuse like heroin. (And there are some reports that the use of heroin is rising again now that Purdue Pharma has done what it should have done many years ago, and reformulated the OxyContin capsule so that it can no longer give the abuser a high by crushing it instead of swallowing it.) And it is true that some studies of the chronic use of opiates for long-term pain have not been as promising as people like me would have hoped. But it still seems to me that there are a lot of patients with severe, untreated or undertreated pain who could benefit from the use of opiates combined with other modalities in a carefully monitored program. And in today's climate where all we hear about in the media are "pill mills" and abuse, it's very hard to get physicians, especially in primary care, to consider such an approach.

So the people at the Wisconsin pain center have unfortunately cast an even deeper shadow over the cause they had hoped to advance, through their willingness to compromise themselves for cash. Even after we consider all the good reasons they may have thought they needed to take the Pharma dollars to get their work done, we see that in the end the risk of taint significantly outweighed whatever good they were able to do. And while you may feel the need to take research and program support funds just to be able to do your work, even that does not justify a personal enrichment relationship such as consulting and speaking.

Tuesday, June 14, 2011

If you want to know the prospects of trimming out-of-control health costs in the US in our lifetimes, you can read the depressing forecast in three articles from the media, all noted in today's Kaiser Family Foundation health policy report.

First let's check out the good news:http://www.minnpost.com/medcitynews/2011/06/13/29088/new_report_finds_health-care_market_awash_in_opportunity--where we learn that there's huge opportunity for profit in the future of health care in America, according to a new report from PricewaterhouseCoopers (linked in the article). Tellingly, the article is titled, "The New Gold Rush." Several types of companies are poised to share the wealth, say the gurus. Some promise actually to help save money through innovative strategies for better management and information flow. But one of the four groups is called "retailers." The description: "Retailers prosper in high-volume, standardized markets with low margins. They use their deep customer relationships and ubiquitous access to serve new markets..."Sound like anyone we know? Notice there's no mention among this group of any contribution to cost containment.

Nick Budnick at The Oregonian tells us about the failure of a legislative provision to try to trim $17M out of the total $240M savings the state needs to achieve in Medicaid. The proposal is consistent with a pile of scientific evidence we've reviewed in several posts here--the general equivalence of older, generic psychiatric medications to newer, more expensive meds.

Defenders of the provision note several things. Other states have developed formularies to cut costs through generic substitution and have achieved similar savings with no apparent downside. It's true that once a complicated patient is stabilized on a particular drug combo, most psychiatrists are leery of messing with success by then trying to switch drugs--so the provision called for exempting patients now on meds and applying only to new patients just starting.

But those sensible observations, and the solid science, could not hold sway against a determined drug industry lobby and their cronies. The industry contributed more than $300,000 to candidates for the state legislature; and to be sure that the so-called patient advocacy groups were on board, the industry also gave $23M to the National Alliance on Mental Illness between 2006 and 2008 (though the state NAMI chapter says it's independent and gets nowhere near that much money). Eventually defenders of the cost-saving provision figured this fight was not worth it and moved on. And this was in Oregon, generally considered one of the most progressive states in the nation.

Here, Jay Bookman in a blog at the Atlanta Journal-Constitution notes that all the opposition to "Obamacare" relies on the ideology that the so-called "free market" will save money for Medicare a lot better than any government plan. So he trots out the data on how free-market systems compare to government run systems in the cost control area, and finds predictably, as any respectable health economist would tell you, that they do much worse.

One telling graph, showing that costs have risen much faster in private insurance than in Medicare between 1969 and 2009, is taken from economist Paul Krugman's blog. Bookman obviously fears a backlash here so he says carefully: "Some will no doubt attempt to discredit the above chart by noting that it originated with Paul Krugman, a Nobel-winning economist and a columnist with the New York Times. However, Krugman built the chart using publicly available and noncontroversial government data, referenced in the caption. If you have grounds to question the accuracy of that data, please do so. Otherwise, you’re attempting to sidestep the issue."

So guess what one of the first comments I saw below the posting said? "Get Real" commented, "You are right Jay; you should have stopped after the words Paul Krugman and the NYT…."

I gather that means that for "Get Real," and others of her/his ilk, the mere fact that something was said by Krugman, or even appeared in the NY Times, is sufficient grounds to dismiss it. When that is what passes for political discourse in the US, then none of the rest of the news we've reviewed here should be of any surprise.

Short version: Sanofi-Aventis makes a drug called Lovenox (enoxaparin), given by injection. This drug is one of a class called "low-molecular-weight heparins." Heparin is a drug to prevent clotting (a so-called "blood thinner" which is a misnomer as it does not thin the blood) that also carries with it a number of problems, including a need to have its effect on the body closely monitored. Lovenox and its cousins can be given safely without that close monitoring, meaning that some conditions that used to require hospital stays now can be handled in an outpatient setting. Lovenox is one of the relatively small number of drugs that could legitimately be argued to have saved money, even though the drug itself is very expensive--if it keeps people out of the hospital and allows home treatment instead.

But all good things must come to an end, and in this case the good thing, for Sanofi-Aventis, is Lovenox's patent. The possibility of competition from cheaper generic drugs cutting into Lovenox's $4B in global sales had the usual effect on the company. Their response has been to launch a massive PR campaign aimed at the FDA, arguing that the data do not demonstrate the safety of the generic versions, raising the fear that patients might die if given cheaper drugs.

As Roy Poses noted in the Health Care Renewal post, a typical PR move in such circumstances is to play the "third-party tactic"-- send the company's message to the FDA but as if it was coming spontaneously from another party entirely, without any prompting from the firm. Now, enter the Senate Finance Committee, where drug industry foe Sen. Charles Grassley hangs out. The committee has issued a report naming two medical societies (Society of Hospital Medicine (SHM), North American Thrombosis Forum (NATF)) and Duke University prof Dr. Victor Tapson as accepting large payments from the company and then sending supposedly independent letters to the FDA challenging the safety of the generic drugs. Internal company memos clearly indicate that the company, at least, thought that it had a quid pro quo from these folks. Between 2007 and 2010, Sanofi-Aventis contributed more than $2.6M to SHM, $2.3M to NATF, and $260,000 to Dr. Tapson. Dr. Tapson was apparently a bargain for the company; he wrote multiple letters to the FDA. Paul Thacker at Project on Government Oversight reports that Dr. Tapson, in an e-mail to the Wall Street Journal, characterized the Senate Finance report as "very incorrect," but did not explain in what way. Thacker throws in as a bonus a copy of one of the letters Dr. Tapson wrote to the FDA (http://pogoarchives.org/m/ph/lovenox-senate-report/tapson-letter-duke-letterhead-20100528.pdf).

And of course in none of the communications from the above three parties was any mention made of receiving funding from Sanofi-Aventis. Earlier, before the Senate Finance report, leaders of one of the medical societies explicitly denied any relationship between the company funding and their letters to the FDA.

Friday, June 10, 2011

Thanks to my pals Rick Bukata and Jerry Hoffman over at Primary Care Medical Abstracts for telling me about this study (subscription required). A team from Naples, Italy led by Dr. Pierluigi Costanzo did a meta-analysis of 41 randomized trials, all of which allowed a comparison between carotid intima-media thickness (IMT) and cardiovascular outcomes.

Let's stop for a plain-English break. You can do a fairly simple, noninvasive ultrasound test and measure thickening in the wall of the carotid artery in the neck. This measure has for a long time been viewed as an aspect of atherosclerosis, or hardening of the arteries--and indeed, if you divide a large population into those with a lot of thickening and those with a little, the former group ends up showing more heart disease in the end. This has led investigators who want to test whether their drug or other treatment works to lower cholesterol and to prevent cardiovascular disease like heart attacks and strokes to measure IMT as their favored outcome measure. The theory is that it might take many years to see a difference among your treatment groups in heart attack, stroke, or death rates; but within a few months to a year you might be able to measure changes in IMT, so it's much quicker and cheaper to measure IMT than to wait for the "hard" clinical endpoints.

The Costanza group sugegsts that there's only one problem with this quick-and-cheap approach. Their meta-analysis showed that there is no consistent relationship between improvements in IMT and any of the outcomes that really matter. In short, IMT is just like too many other "surrogate endpoints" in medical research--just because it gets better, you cannot assume that what really is of interest gets better too. Costanza et al continued to agree with what we thought we knew in the past--that a high IMT at baseline is a risk factor for worse heart or vessel disease on a population basis. It's the later change in IMT that seems not to be correlated with anything of importance. (Just why this is so, they offer a number of possible explanations for, which need not concern us here.)

I have to note in fairness that these meta-analysis results can cut both ways. Guess who wants to do quick and cheap studies to show that a drug works for reducing your cardiovascular risk? Our old friends the drug industry, of course. So showing the lack of any linkage between IMT improvements and real risk reduction means that a number of studies that seemed to show great promise for any given drug are of no real scientific value--no matter how many drugs may have been sold to unwary docs based on those findings. But it also means that a drug that fails to improve IMT could, presumably, still end up being valuable in reducing heart risk. Consider Zetia or ezetimibe (http://brodyhooked.blogspot.com/2008/01/now-that-weve-been-enhanced-whats.html). The manufacturer got stung because they put a lot of weight on a study, ENHANCE, trying to show that their drug reduced IMT, and it ended up maybe making it worse. We now can see that those findings may not have really told us much about whether or not ezetimibe is a good drug. (I understand that the manufacturer is now sponsoring a longer-term study to measure actual outcomes--which of course is what they should have done from the get go.)

In a way this is all a crying shame. It makes really good sense that IMT ought to be a reliable measure of the progression or improvement of atherosclerosis. Physicians and scientists who thought this has to be true are not smoking something; the hypothesis seemed to make excellent physiological sense. And this in turn illustrates a point that's becoming an old refrain in this blog. The Pharma marketers very seldom tell docs something that we all know to be untrue and get us to swallow it. They are, on the other hand, extremely adept at taking something we already believe to be true, even if it isn't, and then using that belief to manipulate us into a course of action that ends up with more revenue in their pockets. So the problem is us fooling ourselves as often as it is them fooling us--or more accurately, us helping them to fool us.

I am not usually pestered with e-mails from consultants who serve the pharmaceutical industry, and so it was an interesting experience to get one e-mail directly and have another forwarded to me by a colleague, within 24 hours. As I described last month--http://brodyhooked.blogspot.com/2011/05/on-care-and-feeding-of-kols-attend.html--the care and feeding of KOLs ("key opinion leaders" for those who just joined us, aka paid physician shills for industry) seems to be a hot topic just now.

I received this message:

Howard,

I hope things are well at University of Texas Medical Branch. As you may already know, the Sunshine Act is the most pressing set of regulations that will impact how companies approach KOL compensation. University of Texas Medical Branch will need to start implementing aggregate spend tracking processes now, because in January 2012, your company will be required to disclose all payments for key opinion leaders' services. Companies like University of Texas Medical Branch need to have a progressive and compliant infrastructure in place to establish fair-market value compensation and meet regulatory challenges. Regulatory agencies that have focused heavily on top drug makers have begun to turn their attention toward mid-size and smaller companies' KOL compensation practices. Cutting Edge Information’s latest study, "KOL Fair-Market Value and Aggregate Spend: Documentation, Tracking and the Sunshine Act," is designed to help companies of all sizes compete in today's highly regulated environment.

Our report contains 1000+ data points and metrics that will help your team:Benchmark FMV payments to set fee schedules and compensation ranges.Understand the impact of new and existing regulations on fair-market value payments.Track highly detailed FMV compensation ranges with the industry-leading level of granularity you need to remain compliant.Learn how other large companies have changed their KOL compensation strategies to stay competitive following the Sunshine Act's passage.Stay compliant with new federal regulations and avoid hefty regulatory fines.Overcome the hurdles erected by third-parties to hinder companies' efforts at building KOL relationships.Build a best-in-class system to aggregate KOL spending data, as well as track and document KOL activities.Has University of Texas Medical Branch done all it can to prepare for the big changes required by the Sunshine Act? We can help - find out more here: http://www.cuttingedgeinfo.com/research/medical-affairs/thought-leader-fmv/If you would like to talk more about how we can customize our benchmarks and analysis to your specific needs, I am more than happy to discuss the array of services we can provide you. I hope to hear from you soon - enjoy your week!

These folks appear to think that the academic medical center I work for is a mid-sized company that sells drugs. We do, I suppose, employ "key opinion leaders" but we call them faculty, and expect them to teach students and do research and take care of patients, not sell products for us. (There is the whole debate about whether academic centers are becoming too commercialized, but that's a different post.) They also seem to suggest that the threat of shining the light of publicity on KOL-related activities will have us running scared and hence in need of consultant assistance.

Meanwhile a colleague of mine received this e-mail solicitation:

Dear XXX,I wanted to get in contact, as we're organizing speakers for a very focused and unique conference looking at the important issue of:

This will be the only focused event looking at the latest "best practice" approaches to selling and marketing high-value specialty drugs to distinct consumer groups, and working in partnership with therapeutic specialists & pharmacists as well as with hospitals & healthcare providers to provide real value and to improve patient access.One of the goals, will be to improve seamless coordination between all internal & external stakeholders in strategic, operational and tactical roles. Such roles would typically include marketing, commercial operations, sales, sales force effectiveness, talent development, training, market access, pricing and reimbursement, product and brand management, as well as medical affairs & liaisons. As specialty & orphan marketplaces are growing rapidly, with a lot of new, high cost therapies entering a saturated market, where payers are more risk averse and budget-conscious, most would agree this topic deserves specific and detailed attention and discussion.Would you perhaps be interested to speak/present there? If not, perhaps you could recommend somebody or a specific organization who we could invite?

Possible topics will include:· Specific examples & focused case studies from across Specialty disease & medical areas i.e. Oncology, Orphan, Inflammatory, Pediatrics + others.· What do specialist prescribers want and how can we better communicate value?· New approaches to customer-centric, ethical, trust-focused, value-based sales of innovative drugs in the face of increasingly available and lower-cost generic products· Best practices in specalist account management· Mapping and targeting Key Opinion Leaders, payers, and today's new stakeholders· Understanding, adapting to and selling in, the new cost containment, health technology assessment, evidence-based environment· Interacting with specialists treating multicultural populations· Increasingly important role of the Medical Science Liaison to engage KOL· Marketing approaches to: Healthcare providers, Hispanic, African- American, Asian-Americans, Women, Parents, Elderly· Digital and social media advances and how to adapt marketing methods to communicate effectively with specialists· Benefits from supporting investigator initiated trials & publications· Responding to the growing need of gathering & presenting real world data to demonstrate product value and acheive market access· How to best incorporate all stakeholders' insight and analysis into company activities· What differences exist for marketing specialty products to niche & emerging markets?

Consultants and solution providers please note: As we have a high demand for speaking positions and very limited positions available, solution providers who sponsor/exhibit will be given first right of refusal for limited speaking opportunities.

I am thrilled that "ethical" got thrown into their laundry list. As best as I can tell, these various firms want to assist companies who now employ KOLs to keep doing what they are doing, which presumably includes making a lot of money, despite a hostile environment in which some people are mean enough to say that the odor arising from these activities is starting to seem a bit rank. There seems to be no one considering telling us that maybe the reason there are problems and stresses is that KOL-related activities are inconsistent with medical professionalism and should be curtailed or completely rethought.

--tells us that 5 senators, including our old acquaintance Chuck Grassley of Iowa, have asked the Inspector General of DHHS to investigate physician-owned distributorships. These PODs are owned by physicians and act as middlemen, buying medical devices such as spinal surgery implants from the manufacturer and selling them to hospitals. They apparently are sometimes able to offer the device at a slight discount, which the owners claim makes them a good thing.

The senators are prompted by press coverage of a Portland, OR case in which a neurosurgeon was charged with doing a lot of unnecessary surgery, which could have been motivated by his being an investor in a POD and making more money the more devices the POD sold (to the tune in that case of a cool half million a year). He denies thart he did any unnecessary surgery but he has lost his privileges and is being investigated by the state medical board. A telling point is that once the POD had the media spotlight shown on it, device manufacturers stopped doing business with it and it had to shut down.

The senators' concern is also prompted by the apparent near-exponential growth in PODs, even though they exist in a "legal gray area" according to Carryrou. (Besides the PODs themselves, another growth industry seems to be law firms promising that they'll help you set up your POD in a way that protects you from the legal system coming down on your head.)

Does anyone recall the olden days, when it was sometimes necessary to explain to physicians why they should not own a drug store on the side, and then send their patients to that drug store with their prescriptions? Maybe time for a refresher course...

Quick summary and attach "allegedly" in front of everything as none of this has been proven--a relatively small German firm, Biotronik, that makes pacemakers and implantable defibrillators, is now answering questions based on a trove of internal documents sent to the New York Times by a disgruntled former employee--an employee who claims he was fired because he complained about the corporate wrongdoing that his documents demonstrate. (The company protests that he's cherry-picked and that the documents don't tell the whole story.) PS-- a little change here in the usual script; usually it's a lawsuit or a Federal investigation for fraud that triggers release of these hidden documents.

The documents reveal a pattern of payola to get cardiologists to use Biotronik devices rather than one of their competitors'. The payola takes the form of "seeding trials"-- trials of no scientific value that are really excuses to get practitioners to enroll "subjects" for fees, and to promote the wider use of the company's product. (Biotronik sales officials even referred to these trials candidly in their internal documents as "unscientific studies.") Hiring physicians or their family members as "consultants" based solely on volume of product used or referrals for product use is the other major activity documented.

Here's a typical passage from Meier: "An implant specialist in Fullerton, Calif., Duane E. Bridges, became a consultant to Biotronik in mid-2008, company records indicate. The monetary volume of company products used by Dr. Bridges from early 2008 to early 2009 reached about $360,000, then jumped to $1.6 million over the next 12-month period, a greater than fourfold rise, the company data indicates. Dr. Bridges did not respond to comment; also a lawyer, Anthony Willoughby, who said he represented Dr. Bridges could not be reached for comment."

Also: "For example, in plotting strategies to gain sales at one California hospital, Biotronik officials suggested that an implant specialist, whose son and wife both worked for a competitor, might be wooed if Biotronik offered him concessions “such as studies or even the hiring of his son,” according to an internal company report."The article also details a non-implanting cardiologist in Tucson, who was hired on as a Biotronik consultant and immediately informed his colleagues that he would not refer patients to them for implants unless they agreed to use Biotronik stuff. One of the area cardiologists to whom this doc referred patients (who was not apparently a paid consultant himself) increased his use of Biotronik devices eightfold, netting the company $1.1M in revenues.

Dr. Poses offers two astute comments. First, he notes that even people critical of financial ties with the drug and device industries tend to be less concerned about consulting relationships, and willing to give the doc the benefit of the doubt that the "consulting" is real and involves a true contribution of expertise in exchange for reasonable pay. He then notes that memos like those exposed here show that from the industry's point of view, "consulting" looks like bribery pure and simple. I would add a footnote--I expect if anything, and some of my surgeon colleagues agree, this is even more true in the device industry than in drugs. Why? Since device makers virtually never sponsor head to head trials, there's no scientific data as a rule as to which device is better. So if three firms sell similar devices, it's a wide-open arms race to get the docs to use your device and not the other guy's. The Biotronik memos seems to make clear that competition with other, bigger firms was the main driver behind these activities. (And incidentally reveals that almost for sure, the other firms were using the same tactics.)

Second point: Dr. Poses notes the by-now-pretty-tired excuse, that financial ties between docs and industry are required to promote scientific advance and innovation. It's quite clear that nothing about this entire Biotronik episode relates in any way to innovation.

Let me add my own two cents and bring up another huge point. Here is how Meier began his story: "The message from cardiologists was loud and clear, according to a top executive at a heart device company. The doctors wanted implant makers to produce more clinical trials of devices to help them generate income from research fees. To compete, 'we must be able to "answer the bell," ' wrote Thomas V. Brown, an executive vice president at the American subsidiary of Biotronik..."

In HOOKED I wrote about what seemed to be to be the saddest depths of professional ethics that physicians could fall to--not drug reps tempting physicians with generous payola to prescribe their products, but greedy physicians actually shaking down the reps for even more goodies and threatening to stop prescribing their drugs if they didn't come across. (To the point where even the drug reps felt ethically offended by the docs' behavior!) One has to conclude that a number of the cardiologists who ended up in the pockets of Biotronik were not seduced there by the big bad corporation; they pretty freely and eagerly crawled in. And what does that tell us about the state of professional ethics when these practices are permitted to flourish?

Daniel Levinson, Inspector General of DHHS, weighs in on their recent report viewing with alarm how many demented elderly are receiving atypical antipsychotic drugs, which Levinsom notes are not approved by the FDA for this use, and can pose serious risks, including a higher death rate. On the other side is Dr. Danny Carlat, whose work has often been noted in this blog.

Dr. Carlat makes a number of good points. He stresses, as I have tried to myself, that "off-label" does not necessarily equal "wrong use" or "bad use" of a drug. He makes the important point that as of now no drug is approved specifically by the FDA for treatment of agitation caused by dementia, despite the way this condition can make life miserable for both patients and families as well as for staff. Moreover, he notes that several clinical trials support this use of antipsychotic medication. He therefore concludes that it's a matter of individual medical judgment whether for any given patient, the potential harms of these drugs are outweighed by the benefits--and OIG should back off.

Given Dr. Carlat's excellent record I hate to quibble with him, especially in an area where his psychiatric smarts trump any medical knowledge that I possess. But I would pose just one question. The atypical antipsychotics seem to pose one unique risk that especially is worrisome for the elderly--weight gain that could trigger diabetes--that is not shared by the older antipsychotics. And recent literature reviews (see for instance http://brodyhooked.blogspot.com/2009/01/are-second-generation-antipsychotic.html) have demonstrated pretty convincingly, I would judge, that there's no real benefit of the newer antipsychotics over the older, to the extent that calling them "second-generation" or "atypical" is probably a serious misnomer. So given that all drug use for this unfortunate problem is going to be off-label anyway, why not use a cheaper, older drug that many primary care physicians understand much better?

I have referred at various times to the problem the drug industry faces of the empty research pipeline, with fewer useful new drugs coming out of their research labs, meaning that if they want to continue making the profits they (and their stockholders) have grown accustomed to, they have no choice but to market the hell out of less-satisfactory drugs. I have also referred to the Medical Letter, a long-term standby for non-commercial drug information for practicing docs, tho sadly so few US practitioners subscribe to it.

The pipeline problem is, I believe, well illustrated by two items from recent Medical Letter issues (May 2 and May 16):

Duloxetine (Cymbalta), basically an antidepressant but one that has been viewed as having a specific anti-pain component, has just been approved for treatment of chronic musculoskeletal pain. ML notes that the mechanism by which duloxetine might relieve pain is unknown, and that the studies supporting its efficacy were all performed by employees of the manufacturer. All studies are placebo-controlled; there is no comparison with either commonly used over-the-counter analgesics, or with other (cheaper) antidepressants. A 30-day supply of Cymbalta costs $160. The reviewers conclude that if duloxetine has any superiority over placebo, it seems to be "modest at best."

Medoxomil (Edarbi) is the 8th drug of the angiotensin receptor blocker class to be marketed. (There is one, losartan, that is now available generically, but interestingly its cost is not that much lower than all the brand name drugs.) Like all other ARBs it works for hypertension. ML admits that medoxomil "might" be more effective than some other ARBs for that condition. But it also has a major practical disadvantage--the tablets are sensitive to light and moisture and so cannot be taken out of their original container until you swallow them. Just why we need yet another ARB, and one that is so difficult to use to boot, is never explained.

I think these examples highlight what the drug industry is up against, due to the lack of real breakthrough drugs these days. While we might have some pity for the poor marketers who have to convince us that these pigs look good in lipstick, that still does not justify the shady marketing practices that we discuss in this blog practically every week.

What we have been calling "Medical education and communications companies" (MECCs) on this side of the pond seem to be called "publication planning agencies" in the UK, but other than that there does not seem to be any trans-Atlantic difference.

The Guardian blogger discovered a considerable degree of what some would call chutzpah among the "publication planners" he spoke with. They talked about providing a real service and moving their activities from the realm of marketing into the realm of science. (Remember the drug rep's, and the physician apologist's, chorus: "It's not marketing, it's education"?) They spoke of a new level of openness in their activities.

All of which was quickly debunked by various expert commentators. The replies included:

Dr Leemon McHenry, medical ethicist at California State University: "They've just found more clever ways of concealing their activities. There's a whole army of hidden scribes. It's an epistemological morass where you can't trust anything."

Alastair Matheson, British medical writer: the planners' claims to having reformed are "bullshit...The new guidelines work very nicely to permit the current system to continue as it has been. The whole thing is a big lie. They are promoting a product."

So just what is going on here? My interpretation: Demands for disclosure appear in this case actually to have backfired, to some degree. The ghostwriters and their handlers used to work strictly in the dark. It then became obvious to them that the very fact that they operated out of sight gave credence to charges that they were up to no good. So they decided that the wiser strategy was to pretend to come out into the daylight. They talk more openly about what they do and crow about what a valuable service it is, thereby creating an aura of transparency.

But there is still no real transparency. They say that they simply "help" the academic guest author to write the paper, when in actuality, it's the same ol' same ol'--the company-directed ghostwritwer writes a detailed draft and if anything, the academic (who's of course "too busy" to be bothered with the whole thing, except to pocket his fee) maybe changes a few words here and there to keep up appearances. And what ends up published is the company's chosen spin, with the academic credibility of the supposed author and his institutional affiliation pasted on. What is never disclosed is the actual amount and type of work on the manuscript that the "ghost" and the "guest" each contributed, or what each was paid by the drug company for their deeds.

Two lessons here--first, demanding disclosure, rather than an end to nefarious practices, may not be a half-way step toward a solution but actually a regressive step. Second, when enough money is involved, expect quick adaptation to new realities, but no basic change in behavior or attitudes.